[ CAS No. 109838-85-9 ] {[proInfo.proName]}

Name: 109838-85-9|(R)-2-Isopropyl-3,6-dimethoxy-2,5-dihydropyrazine|97%
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COA NMR CNMR HPLC LC-MS

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Product Details of [ 109838-85-9 ]

CAS No. :	109838-85-9	MDL No. :	MFCD00040565
Formula :	C₉H₁₆N₂O₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	FCFWEOGTZZPCTO-MRVPVSSYSA-N
M.W :	184.24	Pubchem ID :	736066
Synonyms :

Calculated chemistry of [ 109838-85-9 ]

Physicochemical Properties

Num. heavy atoms :	13
Num. arom. heavy atoms :	0
Fraction Csp3 :	0.78
Num. rotatable bonds :	3
Num. H-bond acceptors :	4.0
Num. H-bond donors :	0.0
Molar Refractivity :	59.45
TPSA :	43.18 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	No
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.46 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.79
Log Po/w (XLOGP3) :	1.36
Log Po/w (WLOGP) :	0.35
Log Po/w (MLOGP) :	0.86
Log Po/w (SILICOS-IT) :	2.4
Consensus Log Po/w :	1.55

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	1.0
Bioavailability Score :	0.55

Water Solubility

Log S (ESOL) :	-1.64
Solubility :	4.21 mg/ml ; 0.0229 mol/l
Class :	Very soluble
Log S (Ali) :	-1.87
Solubility :	2.49 mg/ml ; 0.0135 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-1.9
Solubility :	2.3 mg/ml ; 0.0125 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	4.04

Safety of [ 109838-85-9 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P305+P351+P338	UN#:	N/A
Hazard Statements:	H315-H319-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 109838-85-9 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

Upstream synthesis route of [ 109838-85-9 ]
Downstream synthetic route of [ 109838-85-9 ]

[ 109838-85-9 ] Synthesis Path-Upstream 1~7

1
[ 420-37-1 ]
[ 143673-66-9 ]
[ 109838-85-9 ]

Yield	Reaction Conditions	Operation in experiment
71.5%	Stage #1: at 20℃; for 41 h; Stage #2: With ammonia; water In dichloromethane at 0℃; for 1 h;	Step A: Preparation of (R)-2-isopropyl-3,6-dimethoxy-2,5-dihydropyrazine (1): To a 2 L round-bottomed flask were added (R)-3-isopropylpiperazine-2,5-dione (20.7 g, 133 mmol), Me₃OBF₄ (49.0 g, 331 mmol) and CH₂Cl₂ (500 mL). The slurry was stirred vigorously at room temperature under nitrogen atmosphere. After stirring 18 hours, the slurry became a clear solution with very viscous yellow oil settling on the bottom of the flask. An additional equivalent of Me₃OBF₄ (19.6 g, 133 mmol) was added and the mixture was stirred at room temperature. After 23 hours, the mixture was cooled in an ice bath, and 200 g of ice and 100 mL of concentrated ammonium hydroxide solution (28percent) were added to the reaction mixture. The reaction mixture was stirred in an ice bath for 1 hour. The layers were separated and aqueous layer was extracted with CH₂Cl₂ (250 mL). The combined organic layers were washed with saturated NaHCO₃ solution (2100 mL) and brine (100 mL), dried over K₂CO₃, filtered through a Celite pad, and concentrated under reduced pressure to provide 25.9 g of light brown oil. The crude material was purified by chromatography with 1:4 ether/pentane to provide 17.464 g of compound 1 as a colorless oil (71.5percent yield). ¹H NMR (400 MHz, CDCl₃) δ 4.08-3.94 (m, 3H), 2.95 (s, 3H), 2.87 (s, 3H), 2.30-2.18 (m, 1H), 1.04 (d, J=7.03 Hz, 3H), 0.76 (d, J=6.64 Hz, 3H).

Reference： [1] Organic Process Research and Development, 2005, vol. 9, # 2, p. 185 - 187
[2] Patent: US2006/264431, 2006, A1, . Location in patent: Page/Page column 20-21
[3] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1995, # 2, p. 157 - 166

2
[ 1685-33-2 ]
[ 109838-85-9 ]

Reference： [1] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1995, # 2, p. 157 - 166

3
[ 32402-31-6 ]
[ 109838-85-9 ]

Reference： [1] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1995, # 2, p. 157 - 166

4
[ 640-68-6 ]
[ 109838-85-9 ]

Reference： [1] Organic Process Research and Development, 2005, vol. 9, # 2, p. 185 - 187

5
[ 22838-58-0 ]
[ 109838-85-9 ]

Reference： [1] Organic Process Research and Development, 2005, vol. 9, # 2, p. 185 - 187

6
[ 850312-86-6 ]
[ 109838-85-9 ]

Reference： [1] Organic Process Research and Development, 2005, vol. 9, # 2, p. 185 - 187

7
[ 109838-85-9 ]
[ 7146-15-8 ]

Reference： [1] Acta chemica Scandinavica (Copenhagen, Denmark : 1989), 1996, vol. 50, # 1, p. 54 - 57
[2] Helvetica Chimica Acta, 1993, vol. 76, # 7, p. 2465 - 2472
[3] Tetrahedron Letters, 1992, vol. 33, # 9, p. 1193 - 1196

[ 109838-85-9 ] Synthesis Path-Downstream 1~30

1
[ 3260-88-6 ]
[ 109838-85-9 ]
[ 130633-31-7 ]
[ 130633-33-9 ]
[ 130697-97-1 ]

Reference： [1]Journal of the Chemical Society. Perkin transactions I,1990,p. 2251 - 2254

2
[ 3260-88-6 ]
[ 109838-85-9 ]
[ 144864-73-3 ]
[ 144864-81-3 ]
[ 144864-81-3 ]
[ 144864-82-4 ]
[ 144864-82-4 ]

Reference： [1]Tetrahedron,1992,vol. 48,p. 7527 - 7538

3
[ 24424-99-5 ]
[ 109838-85-9 ]
[ 142573-55-5 ]
[ 142573-57-7 ]

Yield	Reaction Conditions	Operation in experiment
	Yield given. Multistep reaction;

Reference： [1]Bold, Guido; Allmendinger, Thomas; Herold, Peter; Moesch, Luzia; Schaer, Hans-Peter; et al. [Helvetica Chimica Acta, 1992, vol. 75, # 3, p. 865 - 882]

4
[ 109838-85-9 ]
[ 82830-36-2 ]
[ 160999-36-0 ]

Yield	Reaction Conditions	Operation in experiment
84%	With n-butyllithium In tetrahydrofuran; hexane 1.) - 70 deg C, 15 min, 2.) -70 deg C, 6 h; r.t., 1 h;

Reference： [1]Cappon, J. J.; Witters, K. D.; Baart, J.; Verdegem, P. J. E.; Hoek, A. C.; et al. [Recueil des Travaux Chimiques des Pays-Bas, 1994, vol. 113, # 6, p. 318 - 328]

5
[ 109838-85-9 ]
[ 4876-10-2 ]
[ 137354-55-3 ]
[ 137433-07-9 ]

Reference： [1]Chemical and Pharmaceutical Bulletin,1991,vol. 39,p. 2906 - 2909

6
[ 109838-85-9 ]
[ 141103-93-7 ]
[ 141103-95-9 ]

Reference： [1]Journal of the Chemical Society. Chemical communications,1992,p. 404 - 406

7
[ 109838-85-9 ]
[ 142573-55-5 ]
[ 142573-56-6 ]

Yield	Reaction Conditions	Operation in experiment
	With n-butyllithium 1) THF,hexane, -78 deg C, 1 h; 2) THF, RT; Yield given. Multistep reaction;

Reference： [1]Bold, Guido; Allmendinger, Thomas; Herold, Peter; Moesch, Luzia; Schaer, Hans-Peter; et al. [Helvetica Chimica Acta, 1992, vol. 75, # 3, p. 865 - 882]

8
[ 109838-85-9 ]
[ 131858-37-2 ]
[ 160247-84-7 ]

Yield	Reaction Conditions	Operation in experiment
50%	With n-butyllithium In tetrahydrofuran at -20℃;
	Multistep reaction;
	With n-butyllithium In tetrahydrofuran

Reference： [1]Beugelmans, Rene; Bigot, Antony; Zhu, Jieping [Tetrahedron Letters, 1994, vol. 35, # 40, p. 7391 - 7394]
[2]Boger, Dale L.; Zhou, Jiacheng [Journal of Organic Chemistry, 1996, vol. 61, # 12, p. 3938 - 3939]
[3]Boger, Dale L.; Zhou, Jiacheng; Borzilleri, Robert M.; Nukui, Seiji; Castle, Steven L. [Journal of Organic Chemistry, 1997, vol. 62, # 7, p. 2054 - 2069]

9
[ 109838-85-9 ]
[ 141103-93-7 ]
[ 1005-56-7 ]
[ 141103-97-1 ]

Reference： [1]Journal of the Chemical Society. Chemical communications,1992,p. 404 - 406

10
[ 420-37-1 ]
[ 143673-66-9 ]
[ 109838-85-9 ]

Yield	Reaction Conditions	Operation in experiment
71.5%		Step A: Preparation of (R)-2-isopropyl-3,6-dimethoxy-2,5-dihydropyrazine (1): To a 2 L round-bottomed flask were added (R)-3-isopropylpiperazine-2,5-dione (20.7 g, 133 mmol), Me3OBF4 (49.0 g, 331 mmol) and CH2Cl2 (500 mL). The slurry was stirred vigorously at room temperature under nitrogen atmosphere. After stirring 18 hours, the slurry became a clear solution with very viscous yellow oil settling on the bottom of the flask. An additional equivalent of Me3OBF4 (19.6 g, 133 mmol) was added and the mixture was stirred at room temperature. After 23 hours, the mixture was cooled in an ice bath, and 200 g of ice and 100 mL of concentrated ammonium hydroxide solution (28%) were added to the reaction mixture. The reaction mixture was stirred in an ice bath for 1 hour. The layers were separated and aqueous layer was extracted with CH2Cl2 (250 mL). The combined organic layers were washed with saturated NaHCO3 solution (2100 mL) and brine (100 mL), dried over K2CO3, filtered through a Celite pad, and concentrated under reduced pressure to provide 25.9 g of light brown oil. The crude material was purified by chromatography with 1:4 ether/pentane to provide 17.464 g of compound 1 as a colorless oil (71.5% yield). 1H NMR (400 MHz, CDCl3) delta 4.08-3.94 (m, 3H), 2.95 (s, 3H), 2.87 (s, 3H), 2.30-2.18 (m, 1H), 1.04 (d, J=7.03 Hz, 3H), 0.76 (d, J=6.64 Hz, 3H).
69%	In dichloromethane; at 20℃; for 42h;Cooling with ice; Inert atmosphere;	[0561] To a solution of compound 4-01-4 (11 g, 70 mmol) in dichloromethane (500 mL) was added trimethyloxonium tetrafiuorob orate (41.7 g, 282 mmol). The slurry was stirred vigorously at 20C under a nitrogen atmosphere for 18 hours. The slurry became a clear solution with very viscous yellow oil settled on the bottom of the flask, then another 10.4 g (70 mmol) of trimethyloxonium tetrafiuorob orate was added and the mixture was stirred at 20C for 24 hours. The mixture was cooled in an ice bath, and 200 g of ice and 100 mL of concentrated ammonium hydroxide solution (30%) were added. The reaction mixture was stirred in an ice bath for 1 hour. The layers were separated and aqueous layer was extracted with DCM (500 mL2). The combined organic layers were washed with saturated sodium bicarbonate solution (300 mL 2) and brine (300 mL), dried over anhydrous sodium sulfate, filtered through a celite pad, and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether to petroleum ether: ethyl acetate = 10: 1) to afford compound 4-01-5 (9 g, 69% yield) as yellow oil.

Reference： [1]Organic Process Research and Development,2005,vol. 9,p. 185 - 187
[2]Patent: US2006/264431,2006,A1 .Location in patent: Page/Page column 20-21
[3]Patent: WO2019/75259,2019,A1 .Location in patent: Paragraph 0561
[4]Journal of the Chemical Society. Perkin transactions I,1995,p. 157 - 166

11
[ 5324-30-1 ]
[ 109838-85-9 ]
[ 682-30-4 ]
[ 172342-72-2 ]

Yield	Reaction Conditions	Operation in experiment
81%	With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 2h;
26%	Stage #1: (2R)-2,5-dihydro-2-isopropyl-3,6-dimethoxypyrazine With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 0.5h; Stage #2: diethyl 2-bromoethylphosphonate; Diethyl vinylphosphonate In tetrahydrofuran; hexane at -78 - 20℃;	1a 1a) Diethyl {2-[(2S,5R)-5-isopropyl-3,6-dimethoxy-2,5-dihydropyrazin-2-yl]ethyl}phosphonate [Show Image] nBuLi (6.51 mL, 2.5 mol/L in hexanes, 16.3 mmol) was added at -78°C to a solution of (2R)-(-)-2,5-dihydro-3,6-dimethoxy-2-isopropylpyrazin (2.91 mL, 16.3 mmol) in dry THF (30 mL). After 30 min a solution of diethyl (2-bromoethyl)phosphonate (2.84 mL, 15.5 mmol) and diethyl vinylphosphonate (0.13 mL, 0.81 mmol) in dry THF (20 mL) was added drop wise to the mixture. After further 10 min the mixture was warmed to r.t. and concentrated under reduced pressure. The residue was taken up in water (50 mL) and the solution was extracted with ethyl acetate (3 x 50 mL). The combines organic layers were dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, Hex/EE). Yield: m = 1.50 g, 4.31 mmol, 26%. MS (ESipos): m/z = 349 [M+H]+ 1H-NMR (300MHz, CHLOROFORM-d): δ [ppm]= 0.68 (d, 3H), 1.02 (d, 3H), 1.31 (td, 6H), 1.65 - 1.82 (m, 2H), 1.82 - 2.00 (m, 1H), 2.03 - 2.36 (m, 2H), 3.66 (s, 3H), 3.69 (s, 3H), 3.94 (t, 1H), 3.98 - 4.17 (m, 5H).

Reference： [1]Schick, Andreas; Kolter, Thomas; Giannis, Athanassios; Sandhoff, Konrad [Tetrahedron, 1995, vol. 51, # 41, p. 11207 - 11218]
[2]Current Patent Assignee: BAYER AG - EP2322514, 2011, A1 Location in patent: Page/Page column 26-27

12
[ 109838-85-9 ]
[ 15017-52-4 ]
(2S,5R)-2-(4-Fluoro-3-nitro-benzyl)-5-isopropyl-3,6-dimethoxy-2,5-dihydro-pyrazine [ No CAS ]

Reference： [1]Heterocycles,1999,vol. 51,p. 2041 - 2063

13
[ 109838-85-9 ]
[ 172900-69-5 ]
(2S,5R)-2,5-dihydro-3,6-dimethoxy-2-{(2R)-2-[4-methoxy-3-(3-methoxypropoxy)phenyl]methyl}-3-methylbutyl}-5-(1-methylethyl)pyrazine [ No CAS ]
(2R,5R)-2-Isopropyl-3,6-dimethoxy-5-{(R)-2-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-3-methyl-butyl}-2,5-dihydro-pyrazine [ No CAS ]

Reference： [1]Helvetica Chimica Acta,2003,vol. 86,p. 2848 - 2870

14
[ 109838-85-9 ]
[ 172900-69-5 ]
[ 656241-17-7 ]

Reference： [1]Helvetica Chimica Acta,2003,vol. 86,p. 2848 - 2870
[2]Journal of Organic Chemistry,2006,vol. 71,p. 4766 - 4777

15
[ 109838-85-9 ]
[ 67899-04-1 ]
[ 873545-20-1 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: (2R)-2,5-dihydro-2-isopropyl-3,6-dimethoxypyrazine With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 0.75h; Stage #2: ester t-butylique de l'acide 6-iodo hexanoieque In tetrahydrofuran; hexane at -78 - 20℃;	107.1 To a stirred solution of (2R)-2-isopropyl-3,6-dimethoxy-2,5-dihydropyrazine (1.0 eq.) in THF at -78° C., was added dropwise over 10 min a solution of BuLi (1.6 N in hexane, 1.0 eq.) and stirring was continued at -78° C. for 45 min. A pre-cooled solution of tert-butyl 6-iodohexanoate (1.0 eq.) in THF was then added by cannula over 5 min and the reaction stirred overnight, slowly warming to RT. The reaction was then left to stir at RT for a further hour and was quenched by the addition of aqueous NH4Cl solution. The THF layer was decanted off and concentrated under reduced pressure, meanwhile and the aqueous mixture was extracted with EtOAc (3×). The EtOAc extracts were used to redissolve the oily THF residue and this solution was washed with brine, dried (Na2SO4) and concentrated under reduced pressure. The crude was used directly in the next step without further purification (I1).
	Stage #1: (2R)-2,5-dihydro-2-isopropyl-3,6-dimethoxypyrazine With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 0.25h; Stage #2: ester t-butylique de l'acide 6-iodo hexanoieque In tetrahydrofuran; hexane at -78 - 20℃;	fer/-Buty.6-[(2S,5R)-5-isopropyl-3,6-dimethoxy-2,5-dihydropyrazin-2-yl]hexanoate_ (El)_To a stirred solution of (2R)-2-isopropyl-3,6-dimethoxy-2,5-dihydropyrazine (1.0 eq.) in THF at -78°C, a solution of BuLi (1.6 N in hexanes, 1.0 eq.) was added and stirring was continued for 15 min. A precooled solution of tert-butyl 6-iodohexanoate (1.5 eq.) in THF was added and stirring was continued at -78°C for 8 hours. The reaction mixture was allowed to warm to RT overnight. The reaction was quenched by the addition of aqueous NH4CI solution and the mixture extracted with EtOAc. The organic layer was washed with brine, dried (Na2S04) and concentrated under reduced pressure. The crude was purified bycolumn chromatography, eluting with 4% EtOAc /Petroleum ether to afford (El). .H NMR (300 MHz, CDCI3) 8 4.05-3.95 (1H, m), 3.93 (1H, t, J = 3.3 Hz), 3.69 (3H, s), 3.68 (3H, s),2.35-2.14 (3H, m), 1.85-1.55 (2 H, m), 1.44 (9H, s), 1.39-1.15 (6H, m), 1.58 (3H, d, J = 6.7 Hz), 0.69 (3H, d, J = 6.7 Hz). MS (ES) C19H34N2O4requires: 354, found: 355 (M+H*").

Reference： [1]Current Patent Assignee: MERCK & CO INC - US2009/48228, 2009, A1 Location in patent: Page/Page column 63
[2]Current Patent Assignee: MERCK & CO INC - WO2006/5955, 2006, A1 Location in patent: Page/Page column 42

16
[ 398-62-9 ]
[ 109838-85-9 ]
C₁₇H₂₄N₂O₄ [ No CAS ]
[ 1268259-12-6 ]

Reference： [1]Organic Letters,2011,vol. 13,p. 1012 - 1015

17
[ 109838-85-9 ]
[ 52189-63-6 ]
C₁₇H₂₄N₂O₄ [ No CAS ]
[ 1268259-13-7 ]

Reference： [1]Organic Letters,2011,vol. 13,p. 1012 - 1015

18
[ 109838-85-9 ]
[ 82830-49-7 ]
C₁₇H₂₄N₂O₄ [ No CAS ]
[ 1268259-05-7 ]

Reference： [1]Organic Letters,2011,vol. 13,p. 1012 - 1015

19
[ 68470-59-7 ]
[ 2100-42-7 ]
[ 109838-85-9 ]
[ 1365546-39-9 ]

Reference： [1]Beilstein Journal of Organic Chemistry,2011,vol. 7,p. 1570 - 1576

20
[ 109838-85-9 ]
[ 158585-34-3 ]
[ 1334313-93-7 ]

Yield	Reaction Conditions	Operation in experiment
58%	Stage #1: (2R)-2,5-dihydro-2-isopropyl-3,6-dimethoxypyrazine With n-butyllithium In tetrahydrofuran; hexane at -78℃; Stage #2: 1,1-bis(chloromethyl)-1-silacyclopentane In tetrahydrofuran; hexane at -78 - 20℃;	16.B Step B - Preparation of Compound Int-16cTo a 500 mL flame dried flask was added (R)-2-isopropyl-3, 6-dimethoxy-2,5- dihydropyrazine (10.0 g, 54.3 mmol) and anhydrous THF (200 mL). The solution was cooled to -78 °C. «-BuLi (2.5M in hexane, 24.0 mL, 59.7 mmol) was added dropwise. After the solution was allowed to stir at -78 °C for 30 minutes, compound Int-16b (in 5 mL anhydrous THF) was added dropwise. After the solution was allowed to stir at -78 °C for 1 hour, it was allowed to warm up to room temperature in two hours. Water (100 mL) and Et20 (150 mL) were added. The organic layer was separated and the aqueous layer was extracted with Et20 (100 mL) twice. The organic layers were combined, washed with brine, dried over Na2S04, filtered and concentrated in vacuo. The residue obtained was purified using Si02 chromatography (40 g, eluted with Et20 in Hexane: 0% to 3%) to provide compound Int-16c (10.43 g, 58.0%).
58%	Stage #1: (2R)-2,5-dihydro-2-isopropyl-3,6-dimethoxypyrazine With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 0.5h; Stage #2: 1,1-bis(chloromethyl)-1-silacyclopentane In tetrahydrofuran; hexane at -78 - 20℃; for 3h;	16.B To a 500 mL flame dried flask was added (i?)-2-isopropyl-3, 6- dimethoxy-2,5-dihydropyrazine (10.0 g, 54.3 mmol) and anhydrous THF (200 mL). The solution was cooled to -78 °C. «-BuLi (2.5M in hexane, 24.0 mL, 59.7 mmol) was added dropwise. After the solution was allowed to stir at -78 °C for 30 minutes, Compound Int-16b (in 5 mL anhydrous THF) was added dropwise. After the solution was allowed to stir at -78 °C for 1 hour, it was allowed to warm up to room temperature in two hours. Water (100 mL) and Et20 (150 mL) were added. The organic layer was separated and the aqueous layer was extracted with Et20 (100 mL) twice. The organic layers were combined, washed with brine, dried over Na2S04, filtered and concentrated in vacuo. The residue obtained was purified using Si02 chromatography (40 g, eluted with Et20 in Hexane: 0% to 3%) to provide Compound Int-16c (10.43 g, 58.0%).
58%	Stage #1: (2R)-2,5-dihydro-2-isopropyl-3,6-dimethoxypyrazine With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 0.5h; Stage #2: 1,1-bis(chloromethyl)-1-silacyclopentane In tetrahydrofuran; hexane at -78 - 20℃; for 3h;	16.B To a 500 mL flame dried flask was added (R)-2-isopropyl-3, 6-dimethoxy-2,5- dihydropyrazine (10.0 g, 54.3 mmol) and anhydrous THF (200 mL). The solution was cooled to -78 °C. «-BuLi (2.5M in hexane, 24.0 mL, 59.7 mmol) was added dropwise. After the solution was allowed to stir at -78 °C for 30 minutes, Compound Int-16b (in 5 mL anhydrous THF) was added dropwise. After the solution was allowed to stir at -78 °C for 1 hour, it was allowed to warm up to room temperature in two hours. Water (100 mL) and Et20 (150 mL) were added. The organic layer was separated and the aqueous layer was extracted with Et20 (100 mL) twice. The organic layers were combined, washed with brine, dried over Na2S04, filtered and concentrated in vacuo. The residue obtained was purified using Si02 chromatography (40 g, eluted with Et20 in Hexane: 0% to 3%) to provide Compound Int-16c (10.43 g, 58.0%).

58%	Stage #1: (2R)-2,5-dihydro-2-isopropyl-3,6-dimethoxypyrazine With n-butyllithium In tetrahydrofuran; hexane at -78℃; Stage #2: 1,1-bis(chloromethyl)-1-silacyclopentane In tetrahydrofuran; hexane at -78 - 20℃;	16.B Step B - Preparation of Compound Int-16cTo a 500 mL flame dried flask was added (R)-2-isopropyl-3, 6-dimethoxy-2,5- dihydropyrazine (10.0 g, 54.3 mmol) and anhydrous THF (200 mL). The solution was cooled to -78 °C. «-BuLi (2.5M in hexane, 24.0 mL, 59.7 mmol) was added dropwise. After the solution was allowed to stir at -78 °C for 30 minutes, compound Int-16b (in 5 mL anhydrous THF) was added dropwise. After the solution was allowed to stir at -78 °C for 1 hour, it was allowed to warm up to room temperature in two hours. Water (100 mL) and Et20 (150 mL) were added. The organic layer was separated and the aqueous layer was extracted with Et20 (100 mL) twice. The organic layers were combined, washed with brine, dried over Na2S04, filtered and concentrated in vacuo. The residue obtained was purified using Si02 chromatography (40 g, eluted with Et20 in Hexane: 0% to 3%) to provide compound Int-16c (10.43 g, 58.0%).
58%	Stage #1: (2R)-2,5-dihydro-2-isopropyl-3,6-dimethoxypyrazine With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 0.5h; Stage #2: 1,1-bis(chloromethyl)-1-silacyclopentane In tetrahydrofuran; hexane at -78 - 20℃; for 3h;	32.B Step B - Synthesis of Intermediate Compound Int-32c Step B - Synthesis of Intermediate Compound Int-32c (0421) To a 500 mL flame dried flask was added (R)-2-isopropyl-3, 6-dimethoxy-2,5-dihydropyrazine (10.0 g, 54.3 mmol) and anhydrous THF (200 mL). The solution was cooled to -78 °C. n-BuLi (2.5M in hexane, 24.0 mL, 59.7 mmol) was added dropwise. After the solution was allowed to stir at -78 °C for 30 minutes, Int-32b (in 5 mL anhydrous THF) was added dropwise. After the solution was allowed to stir at -78 °C for 1 hour, it was allowed to warm up to room temperature in two hours. Water (100 mL) and Et2O (150 mL) were added. The organic layer was separated and the aqueous layer was extracted with Et2O (100 mL) twice. The organic layers were combined, washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The resulting residue was purified using flash chromatography on silica gel (40 g, eluted with Et2O in Hexane: 0% to 3%) to provide Compound Int-32c (10.43 g, 58.0%).

Reference： [1]Current Patent Assignee: MERCK & CO INC - WO2012/41227, 2012, A1 Location in patent: Page/Page column 95
[2]Current Patent Assignee: MERCK & CO INC - WO2012/41014, 2012, A1 Location in patent: Page/Page column 121
[3]Current Patent Assignee: MERCK & CO INC - WO2012/40923, 2012, A1 Location in patent: Page/Page column 102 Current Patent Assignee: MERCK & CO INC - WO2012/50848, 2012, A1 Location in patent: Page/Page column 102
[4]Current Patent Assignee: MERCK & CO INC - WO2012/40924, 2012, A1 Location in patent: Example 16
[5]Current Patent Assignee: MERCK & CO INC - EP2545060, 2015, B1 Location in patent: Paragraph 0421

21
[ 216755-57-6 ]
[ 109838-85-9 ]
[ 1620084-30-1 ]

Yield	Reaction Conditions	Operation in experiment
77%		To (R)-2,5-dihydro-3,6-dimethoxy-2-isopropylpyrazine (2 mL, 11.03 mmol) in THF (90 mL) at -78 C was added n-BuLi (1.6 M in hexanes solution, 7.5 mL, 12 mmol). After stirring for 30 min, l-bromo-3-(bromomethyl)-5-fluorobenzene (2.68 g, 10 mmol) in THF (10 mL) was added dropwise over 30 min. The temperature was maintained at -78 C for 30 min then allowed to warm to ambient temperature. After stirring for 16 h, saturated aqueous NH4C1 (30 mL) was added followed by dilution with EtOAc and H20. The THF was removed in vacuo and the remaining organics were separated and dried over sodium sulfate. After removal of solvent, thecrude product was purified by silica gel chromatography to provide (2S,5R)-2-(3-bromo-5- fluorobenzyl)-5-isopropyl-3,6-dimethoxy-2,5-dihydropyrazine (3.17 g, 77%). MS (m/z) 371 [M+H]+

Reference： [1]Patent: WO2014/110296,2014,A1 .Location in patent: Paragraph 0200; 0204

22
[ 109838-85-9 ]
[ 76283-09-5 ]
C₁₆H₂₀BrFN₂O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
60%		Step 1: Synthesis of Intermediate 1-11.1 R24 (212 g, 1151 mmol) in tetrahydrofuran (dry) (600 mL) is cooled to -78C. Then n-butyllithium (2.5 M in hexanes, 552 mL, 1381 mmol) is added dropwise, keeping the temperature below -78C. After 30 min R25 (324g, 1209 mmol) in tertahydrofurane (dry) (120 mL) is added dropwise. The reaction mixture is stirred at -78C for 1 h. The mixture is quenched with saturated NH4C1 solution and extracted three times with ethyl acetate. The organic layer is washed with brine, dried over Na2S04 and evaporated in vacuo. The residue is purified by flash chromatography (heptane/ ethyl acetate = 80/20). Yield 60%.
60%		R8 (212 g, 1151 mmol) in tetrahydrofuran (dry) (600 mL) is cooled to -78C. Then n-butyllithiwn (2.5 Min hexanes, 552 mL, 1381 mmol) is added dropwise, keeping the temperature below -78C.After 30 min R9 (324g, 1209 mmol) in tertahydrofuran (dry) (120 mL) is added dropwise. Thereaction mixture is stirred at -78C for 1 b. The mixture is quenched with saturated NILCI solutionand extracted three times with ethyl acetate. The organic layer is washed with brine, dried overNa2S04 and evaporated in vacuo. The residue is purified by flash chromatography (heptane/ ethyl10 acetate = 80/20). Yield 60%.
60%		R8 (212 g, 1151 mmol) in tetrahydrofuran (dry) (600 mL) is cooled to -78 C. Then n-butyllithium (2.5 M in hexanes, 552 mL, 1381 mmol) is added dropwise, keeping the temperature below -78 C. After 30 min R9 (324 g, 1209 mmol) in tetrahydrofuran (dry) (120 mL) is added dropwise. The reaction mixture is stirred at -78 C. for 1 h. The mixture is quenched with saturated NH4Cl solution and extracted three times with ethyl acetate. The organic layer is washed with brine, dried over Na2SO4 and evaporated in vacuo. The residue is purified by flash chromatography (heptane/ethyl acetate=80/20). Yield 60%.

60%		Step 1: Synthesis of Intermediate 1-4.1R8 (212 g, 1151 mmol) in tetrahydrofuran (dry) (600 mL) is cooled to -78C. Then n-butyllithium(2.5 M in hexanes, 552 mL, 1381 mmol) is added dropwise, keeping the temperature below -78C.After 30 mm R9 (324g, 1209 mmol) in tertahydrofuran (dry) (120 mL) is added dropwise. Thereaction mixture is stirred at -78C for 1 h. The mixture is quenched with saturated NH4C1 solutionand extracted three times with ethyl acetate. The organic layer is washed with brine, dried overNa2SO4 and evaporated in vacuo. The residue is purified by flash chromatography (heptane/ ethyl acetate = 80/20). Yield 60%.
60%		R8 (212 g, 1151 mmol) in tetrahydrofuran (dry) (600 mL) is cooled to -78 C. Then n-butyllithium (2.5 M in hexanes, 552 mL, 1381 mmol) is added dropwise, keeping the temperature below -78 C. After 30 min R9 (324 g, 1209 mmol) in tertahydrofuran (dry) (120 mL) is added dropwise. The reaction mixture is stirred at -78 C. for 1 h. The mixture is quenched with saturated NH4Cl solution and extracted three times with ethyl acetate. The organic layer is washed with brine, dried over Na2S04 and evaporated in vacuo. The residue is purified by flash chromatography (heptane/ethyl acetate=80/20). Yield 60%
60%		(2R)-(-)-2,5-Dihydro-3,6-dimethoxy-2-isopropylpyrazine (212 g, 1151 mmol) in dry tetrahydrofuran (600 mL) is cooled to -78 C. Then n-butyllithium (2.5 M in hexanes, 552 mL, 1381 mmol) is added dropwise, keeping the temperature below -78 C. After 30 min <strong>[76283-09-5]4-bromo-2-fluorobenzyl bromide</strong> (324 g, 1209 mmol) in dry tetrahydrofurane (120 mL) is added dropwise. The reaction mixture is stirred at -78 C. for 1 h. The mixture is quenched with saturated NH4Cl solution and extracted three times with ethyl acetate. The organic layer is washed with brine, dried over Na2SO4, filtered and evaporated in vacuo. The residue is purified by flash chromatography (heptane/ethyl acetate=80/20). Yield 60%.

Reference： [1]Patent: WO2014/140075,2014,A1 .Location in patent: Page/Page column 196
[2]Patent: WO2014/140081,2014,A1 .Location in patent: Page/Page column 72
[3]Patent: US2014/275159,2014,A1 .Location in patent: Paragraph 0304; 0305
[4]Patent: WO2014/140091,2014,A1 .Location in patent: Page/Page column 68
[5]Patent: US2014/275155,2014,A1 .Location in patent: Paragraph 0312; 0313
[6]Patent: US2016/75704,2016,A1 .Location in patent: Paragraph 0215

23
[ 109838-85-9 ]
[ 159275-17-9 ]
benzyl 4-(((2S,5R)-5-isopropyl-3,6-dimethoxy-2,5-dihydropyrazin-2-yl)methyl) piperidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
1.5 g	With n-butyllithium; In tetrahydrofuran; at 20℃; for 4h;Inert atmosphere;	To a 100 ml three neck round bottomed flask under nitrogen atmosphere, (R)-2- isopropyl-3,6-dimethoxy-2,5-dihydropyrazine (3 g, 16.01 mmol) was dissolved in dry THF (40 ml) and cooled to -78 C. To the reaction mixture, 2.5 M n-BuLi in hexanes (9.6 ml, 24.0 mmol) was added dropwise and stirred at -78 C for 30 minutes. After 30 minutes, benzyl 4- (bromomethyl)-piperidine-l -carboxylate (5 g, 16.0 mmol) in dry THF (20 ml) was added dropwise and stirred at -78 C for 30 minutes followed by 4 h at rt. The reaction mixture was quenched with saturated ammonium chloride solution and extracted with ethyl acetate. Combined organic layer was washed with water and brine solution. Organic layer was dried over sodium sulfate and concentrated under vacuum before purification by column chromatography to get 1 .5 g of benzyl 4-(((2S,5R)-5-isopropyl-3,6-dimethoxy-2,5-dihydropyrazin-2-yl)methyl) piperidine-l -carboxylate

Reference： [1]Patent: WO2015/195950,A1 .Location in patent: Page/Page column 82
Patent: ,2015, .Location in patent: Page/Page column 82

24
[ 40422-70-6 ]
[ 109838-85-9 ]
(2S,5R)-2-(3-bromophenethyl)-5-isopropyl-3,6-dimethoxy-2,5-dihydropyrazine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
41.38%		To a 100 mL three neck round bottomed flask under nitrogen atmosphere, (R)-2- isopropyl-3,6-dimethoxy -2,5- dihydropyrazine (4 g, 21.7 mmol) was dissolved in dry THF (28 mL) and cooled to -78 C. To this reaction mixture, 1.6 M solution of n-BuLi in hexanes (16.28 mL, 26 mmol) was added dropwise at -78 C and stirred at same temperature for 15 minutes. After 15 minutes, l-bromo-3- (2-bromoethyl)benzene (5.73 g, 21.7 mmol) in dry THF (13 mL) was added dropwise at -78 C and stirred at -78 C for 1 h followed by stirring at room temperature (rt) for 3 h. The reaction was monitored by TLC using ethyl acctatc hcxancs (0.3:9.7) as a mobile phase. After completion of the reaction, reaction mixture was quenched with saturated ammonium chloride solution (75 mL) and extracted using ethyl acetate (3 x 100 mL). Combined organic layer was dried over sodium sulphate and concentrated to give crude which was purified by flash column purification with 1-3 % ethyl acetate in hexanes to yield 3.3 g of (2S,5R)-2-(3-bromophenethyl)-5- isopropyl-3, 6-dimethoxy-2,5-dihydropyrazine (41.38% yield).
3.3 g	With n-butyllithium; In tetrahydrofuran; at 20℃; for 3h;Inert atmosphere;	To a 100 ml three neck round bottomed flask under nitrogen atmosphere, (R)-2- isopropyl-3,6-dimethoxy-2,5-dihydropyrazine (4 g, 21.7 mmol) was dissolved in dry THF (28 ml) and cooled to -78 C. To this reaction mixture, 1 .6 M solution of n-BuLi in hexanes (16.3 ml, 26 mmol) was added dropwise at -78 C and stirred for 15 minutes. A solution of l-bromo-3- (2-bromoethyl)benzene (5.73 g, 21 .7 mmol) in dry THF (13 ml) was added dropwise at -78 C and stirred for 1 h followed by stirring at rt for 3 h. The reaction mixture was quenched with saturated ammonium chloride solution and extracted using ethyl acetate. The combined organic layer was dried over sodium sulfate and concentrated and purified by flash column purification with 1 -3 % ethyl acetate in hexanes to yield 3.3 g of (2S,5R)-2-(3-bromophenethyl)-5-isopropyl- 3,6-dimethoxy-2,5-dihydropyrazine.

Reference： [1]Patent: WO2019/99576,2019,A1 .Location in patent: Paragraph 0200
[2]Patent: WO2015/195950,A1 .Location in patent: Page/Page column 66;67
Patent: ,2015, .Location in patent: Page/Page column 66;67

25
[ 448968-52-3 ]
[ 109838-85-9 ]
methyl (S)-2-amino-3-(6-nitropyridin-3-yl)propionate [ No CAS ]

Reference： [1]Journal of the American Chemical Society,2017,vol. 139,p. 4611 - 4614

26
[ 448968-52-3 ]
[ 109838-85-9 ]
(2R,5S)-3,6-dimethoxy-2-isopropyl-5-((6-nitropyridin-3-yl)methyl)-2,5-dihydropyrazine [ No CAS ]

Reference： [1]Journal of the American Chemical Society,2017,vol. 139,p. 4611 - 4614

27
[ 2076-88-2 ]
[ 109838-85-9 ]
(2S,5R)-2-((1-benzo[b]thiophen-2-yl)methyl)-3,6-dimethoxy-5-(propan-2-yl)-2,5-dihydropyrazine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: (2R)-2,5-dihydro-2-isopropyl-3,6-dimethoxypyrazine With n-butyllithium In tetrahydrofuran; hexane at -70℃; for 0.5h; Stage #2: 2-chloromethylbenzo[b]thiophene In tetrahydrofuran; hexane at -70℃; for 2h; stereoselective reaction;	(2S,5R)-2-((1-Benzo[b]thiopen-2-yl)methyl)-3,6-dimethoxy-5-(propan-2-yl)-2,5-dihyropyrazine (15) To a solution of (2R)-3,6-dimethoxy-2-(propan-2-yl)-2,5-dihydropyrazine (1.8 mL, 10 mmol) in THF at -70 °C was added dropwise nBuLi hexane solution (6.9 mL, 11 mmol). The resulting solution was stirred for 30 minutes. A solution of 9 (0.9 g, 5 mmol) in THF (7 mL) was introduced via a syringe. The mixture was stirred for 2 hours. The reaction was warmed to -10 °C and quenched with 5% citric acid aqueous solution (15 mL). Volatiles were removed and the remaining content was partitioned with EtOAc (150 mL). The organic layer was separated and washed with 5% citric acid aqueous solution (2 x 15 mL), brine (1 x 15 mL), 5% Na2CO3 aqueous solution (3 x 7 mL), and brine (2 x 15 mL). The solution was dried and evaporated to afford a yellow solid (2.5 g). It was purified by silica gel chromatography (58 g). Elution with up to 1% EtOAc in hexane yielded the desired product 15 (1.45 g, 88%) as a white powder. ESI-MS m/z 330.1402 (C18H22N2O2S), observed m/z 331.3005 [M+H]+. Optical rotation [α]D26 = 48.4 (c 0.5, THF). 1H NMR (600 MHz, CDCl3): δ 8.00 (1H, d, 7.6 Hz), 7.93 (1H, d, 7.6 Hz), 7.52 (3H, m), 4.63 (1H, m), 4.05 (3H, s), 4.00 (3H, s), 3.97 (1H, t, 3.7Hz), 3.64-3.76 (2H, m), 2.48 (1H, m), 1.25 (3H, d, 6.6Hz), 0.95 (3H, d, 6.6Hz) ppm. 13C NMR (600 MHz, CDCl3): δ 164.56, 161.87, 140.58, 140.26, 139.62, 123.77, 123.38, 122.96, 121.92, 60.89, 55.85, 52.64, 52.28, 35.45, 31.67, 18.94, 16.60 ppm.

Reference： [1]Chauhan, Satendra S.; Shang, Suisheng; Pennington, Michael W. [Tetrahedron Letters, 2017, vol. 58, # 46, p. 4388 - 4390]

28
[ 109838-85-9 ]
[ 885681-96-9 ]
C₁₆H₂₀BrIN₂O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
70%		The chiral auxiliary group (2.12 g, 11.5 mmol) was dissolved in dry THF solution (10 mL) and cooled to -78 o.n-Butyllithium reagent (2.5 M in hexane, 5.5 mL,13.8 mmol) was added dropwise to the reaction system and reacted at -78 C for 30 minutes.Add the substrate (3.24 g, 12.1 mmol) in dry THF (10 mL).-78 oC reaction for 60 minutes. After the reaction system is quenched with saturated brine,Take it out from the -78 oC environment and naturally rise to room temperature.It was then extracted 3 times with ethyl acetate (30 mL x 3). Combine the organic phase,Backwash twice with saturated brine (50 mL x 2), dry over anhydrous magnesium sulfate.Filter and concentrate. Obtaining crude product by column chromatography for separation and purification(ethyl acetate: n-hexane = 1: 6), the product was obtained as a pale yellow solid.The yield is 3.85 g,Yield 70%,

Reference： [1]Patent: CN109384806,2019,A .Location in patent: Paragraph 0019; 0020

29
[ 4117-09-3 ]
[ 109838-85-9 ]
C₁₆H₂₈N₂O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
55%	With n-butyllithium; In tetrahydrofuran; at -70 - 20℃;Inert atmosphere;	[0562] A solution of compound 4-01-5 (8.9 g, 48 mmol) in tetrahydrofuran (100 mL) was cooled to -70C and n-butyl lithium (2.5 M, 19.5 mL, 49 mmol) was added under nitrogen while the temperature was kept below -70C. A solution of compound 7- bromohept-l-ene (8.0 g, 45 mmol) in tetrahydrofuran (15 mL) was added at -70C. The reaction mixture was stirred at -70C for 2 hours, then slowly heated to 20C and stirred for 1 hour. The reaction mixture was poured into saturated ammonium chloride solution (50 mL) and extracted with ethyl acetate (200 mL 2). The combined organic phase was washed with brine (100 mL2), dried over anhydrous sodium sulfate, and concentrated in reduced pressure. The residue was purified by column chromatography (petroleum ether to petroleum ether: ethyl acetate = 50: 1) to afford compound 4-01-6 (7 g, 55% yield) as a colorless oil.

Reference： [1]Patent: WO2019/75259,2019,A1 .Location in patent: Paragraph 0562

30
[ 109838-85-9 ]
[ 3814-34-4 ]
(2S,5R)-2-(2-ethylbutyl)-3,6-dimethoxy-5-(propan-2-yl)-2,5 -dihydropyrazine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: (2R)-2,5-dihydro-2-isopropyl-3,6-dimethoxypyrazine With n-butyllithium In tetrahydrofuran at -78℃; for 0.25h; Stage #2: 2-ethyl-1-bromobutane In tetrahydrofuran at -78 - 20℃;	103A (2S,5R)-2-(2-Ethylbutyl)-3,6-dimethoxy-5-(propan-2-yl)-2,5-dihydropyrazine (2R)-3,6-Dimethoxy-2-(propan-2-yl)-2,5-dihydropyrazine (CAS-RN: 109838-859, 2.9 mL, 16 mmol) was dissolved in anhydrous THF (60 mL, 740 mmol) and the solution was cooled to -78°C. n-Butyllithium (10 mL, 1.6 M, 16 mmol) was added dropwise slowly and dropwise over a 15 minute period while stirring at -78°C. 3-(Bromomethyl)pentane (5.91 g, 35.8 mmol) was added and the reaction mixture was stirred for 2 h at -78°C, then allowed to come to room temperature overnight. The solution was cooled to 0oC and slowly quenched with water. Diethyl ether was added and after stirring several minutes, the organic layer was separated. The aqueous phase was extracted two times with diethyl ether. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and evaporated. The crude product was purified by chromatography on silica gel (cyclohexane / ethyl acetate 2%) to give 2.60 g (95 % purity, 57 % yield) of the title compound. LC-MS (Method 10): Rt = 2.90 min; MS (ESI pos): m/z = 269 [M+H]+ H-NMR (400 MHz, DMSO-d6) d [ppm]: -0.008 (0.51), 0.008 (0.45), 0.608 (6.77), 0.624 (6.91), 0.771 (3.04), 0.790 (7.57), 0.796 (3.51), 0.808 (4.20), 0.815 (7.45), 0.833 (3.54), 0.999 (6.56), 1.016 (6.71), 1.179 (0.65), 1.197 (0.97), 1.215 (0.95), 1.223 (0.51), 1.232 (0.73), 1.240 (0.81), 1.257 (1.26), 1.275 (1.64), 1.294 (1.28), 1.310 (0.57), 1.343 (0.55), 1.356 (1.67), 1.364 (0.66), 1.369 (0.83), 1.376 (1.52), 1.388 (1.40), 1.398 (0.66), 1.403 (0.63), 1.409 (1.04), 1.422 (0.43), 1.459 (0.56), 1.474 (0.63), 1.489 (0.45), 1.637 (0.66), 1.647 (0.68), 1.656 (0.56), 1.667 (0.69), 1.670 (0.69), 1.681 (0.54), 1.690 (0.48), 1.700 (0.44), 2.191 (0.54), 2.199 (0.55), 2.208 (0.71), 2.216 (0.71), 2.225 (0.52), 2.233 (0.51), 3.597 (16.00), 3.616 (15.85), 3.916 (1.08), 3.925 (2.24), 3.933 (1.46), 3.959 (0.67), 3.969 (1.06), 3.980 (0.99), 3.990 (1.00), 4.000 (0.49).

Reference： [1]Current Patent Assignee: BAYER AG - WO2020/225095, 2020, A1 Location in patent: Page/Page column 204-205

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P341	If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P342	If experiencing respiratory symptoms:
P350	Gently wash with plenty of soap and water.
P351	Rinse cautiously with water for several minutes.
P352	Wash with plenty of soap and water.
P353	Rinse skin with water/shower.
P360	Rinse immediately contaminated clothing and skin with plenty of water before removing clothes.
P361	Remove/Take off immediately all contaminated clothing.
P362	Take off contaminated clothing and wash before reuse.
P363	Wash contaminated clothing before reuse.
P370	In case of fire:
P371	In case of major fire and large quantities:
P372	Explosion risk in case of fire.
P373	DO NOT fight fire when fire reaches explosives.
P374	Fight fire with normal precautions from a reasonable distance.
P376	Stop leak if safe to do so. Oxidising gases (section 2.4) 1
P377	Leaking gas fire: Do not extinguish, unless leak can be stopped safely.
P378
P380	Evacuate area.
P381	Eliminate all ignition sources if safe to do so.
P390	Absorb spillage to prevent material damage.
P391	Collect spillage. Hazardous to the aquatic environment
P301 + P310	IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician.
P301 + P312	IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell.
P301 + P330 + P331	IF SWALLOWED: Rinse mouth. Do NOT induce vomiting.
P302 + P334	IF ON SKIN: Immerse in cool water/wrap in wet bandages.
P302 + P350	IF ON SKIN: Gently wash with plenty of soap and water.
P303 + P361 + P353	IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower.
P304 + P312	IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell.
P304 + P340	IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing.
P304 + P341	IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P305 + P351 + P338	IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing.
P306 + P360	IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes.
P307 + P311	IF exposed: call a POISON CENTER or doctor/physician.
P308 + P313	IF exposed or concerned: Get medical advice/attention.
P309 + P311	IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician.
P332 + P313	IF SKIN irritation occurs: Get medical advice/attention.
P333 + P313	IF SKIN irritation or rash occurs: Get medical advice/attention.
P335 + P334	Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages.
P337 + P313	IF eye irritation persists: Get medical advice/attention.
P342 + P311	IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician.
P370 + P376	In case of fire: Stop leak if safe to Do so.
P370 + P378	In case of fire:
P370 + P380	In case of fire: Evacuate area.
P370 + P380 + P375	In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion.
P371 + P380 + P375	In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion.
Storage
Code	Phrase
P401
P402	Store in a dry place.
P403	Store in a well-ventilated place.
P404	Store in a closed container.
P405	Store locked up.
P406	Store in corrosive resistant/ container with a resistant inner liner.
P407	Maintain air gap between stacks/pallets.
P410	Protect from sunlight.
P411
P412	Do not expose to temperatures exceeding 50 oC/ 122 oF.
P413
P420	Store away from other materials.
P422
P402 + P404	Store in a dry place. Store in a closed container.
P403 + P233	Store in a well-ventilated place. Keep container tightly closed.
P403 + P235	Store in a well-ventilated place. Keep cool.
P410 + P403	Protect from sunlight. Store in a well-ventilated place.
P410 + P412	Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF.
P411 + P235	Keep cool.
Disposal
Code	Phrase
P501	Dispose of contents/container to ...
P502	Refer to manufacturer/supplier for information on recovery/recycling

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Physical hazards
Code	Phrase
H200	Unstable explosive
H201	Explosive; mass explosion hazard
H202	Explosive; severe projection hazard
H203	Explosive; fire, blast or projection hazard
H204	Fire or projection hazard
H205	May mass explode in fire
H220	Extremely flammable gas
H221	Flammable gas
H222	Extremely flammable aerosol
H223	Flammable aerosol
H224	Extremely flammable liquid and vapour
H225	Highly flammable liquid and vapour
H226	Flammable liquid and vapour
H227	Combustible liquid
H228	Flammable solid
H229	Pressurized container: may burst if heated
H230	May react explosively even in the absence of air
H231	May react explosively even in the absence of air at elevated pressure and/or temperature
H240	Heating may cause an explosion
H241	Heating may cause a fire or explosion
H242	Heating may cause a fire
H250	Catches fire spontaneously if exposed to air
H251	Self-heating; may catch fire
H252	Self-heating in large quantities; may catch fire
H260	In contact with water releases flammable gases which may ignite spontaneously
H261	In contact with water releases flammable gas
H270	May cause or intensify fire; oxidizer
H271	May cause fire or explosion; strong oxidizer
H272	May intensify fire; oxidizer
H280	Contains gas under pressure; may explode if heated
H281	Contains refrigerated gas; may cause cryogenic burns or injury
H290	May be corrosive to metals
Health hazards
Code	Phrase
H300	Fatal if swallowed
H301	Toxic if swallowed
H302	Harmful if swallowed
H303	May be harmful if swallowed
H304	May be fatal if swallowed and enters airways
H305	May be harmful if swallowed and enters airways
H310	Fatal in contact with skin
H311	Toxic in contact with skin
H312	Harmful in contact with skin
H313	May be harmful in contact with skin
H314	Causes severe skin burns and eye damage
H315	Causes skin irritation
H316	Causes mild skin irritation
H317	May cause an allergic skin reaction
H318	Causes serious eye damage
H319	Causes serious eye irritation
H320	Causes eye irritation
H330	Fatal if inhaled
H331	Toxic if inhaled
H332	Harmful if inhaled
H333	May be harmful if inhaled
H334	May cause allergy or asthma symptoms or breathing difficulties if inhaled
H335	May cause respiratory irritation
H336	May cause drowsiness or dizziness
H340	May cause genetic defects
H341	Suspected of causing genetic defects
H350	May cause cancer
H351	Suspected of causing cancer
H360	May damage fertility or the unborn child
H361	Suspected of damaging fertility or the unborn child
H361d	Suspected of damaging the unborn child
H362	May cause harm to breast-fed children
H370	Causes damage to organs
H371	May cause damage to organs
H372	Causes damage to organs through prolonged or repeated exposure
H373	May cause damage to organs through prolonged or repeated exposure
Environmental hazards
Code	Phrase
H400	Very toxic to aquatic life
H401	Toxic to aquatic life
H402	Harmful to aquatic life
H410	Very toxic to aquatic life with long-lasting effects
H411	Toxic to aquatic life with long-lasting effects
H412	Harmful to aquatic life with long-lasting effects
H413	May cause long-lasting harmful effects to aquatic life
H420	Harms public health and the environment by destroying ozone in the upper atmosphere

[ CAS No. 109838-85-9 ] {[proInfo.proName]}

Quality Control of [ 109838-85-9 ]

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[ 109838-85-9 ] Synthesis Path-Upstream 1~7

[ 109838-85-9 ] Synthesis Path-Downstream 1~30

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Ethers

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[ 109838-85-9 ]